Sickle cell anemia is a devastating disease affecting primarily African Americans. Our goals are to capture the genetic diversity that is likely to underlie the notoriously heterogeneous clinical course of this disease, and with this information, develop predictive network models that will allow us to foretell the likelihood of its severe vasculopathic complications and which patients might be most likely to have early mortality. Consistent with the importance of vasculopathic complications in the pathogenesis of sickle cell disease, candidate gene association studies and preliminary analysis of genome-wide association studies have identified genetic polymorphisms in canonical pathways regulating proliferative vascular responses to injury, like the TGF-[unreadable]/BMP pathway. Furthermore, using an integrated estimate of disease severity as a phenotype, important survivor gene variants that appear to be modulators of the normal, non-sickle cell disease, aging process were found. Once again, these polymorphisms mark genes regulating vascular function. To accomplish our goals we have assembled a new consortium of established investigators and the largest contemporary patient databases and biological sample repository along with the necessary laboratory and analytical capabilities. This group includes Mark Gladwin, Marilyn Telen, and Martin Steinberg, working with Clinton Baldwin in our high throughput genetics laboratory and Paola Sebastiani who leads the effort in Bayesian network modeling. With our established resources, we will directly examine genotype-phenotype relationships focusing on five major sub-phenotypes. The results have the potential to transform not only the sickle cell field, but also provide unique and generalizable insights into the fundamental vascular responses to inflammatory, oxidative and hemolytic stress. We propose that sickle cell disease represents a "crucible" of vascular stress that sharply identifies genetic variants that may broadly regulate: 1) proliferative vascular responses in the systemic and pulmonary vasculature;2) vascular responses to aging;3) the intrinsic propensity of red cells to hemolyze;4) the control of HbF production. Further genotyping will allow us to validate our prior genotype-phenotype associations in sickle cell anemia. Resequencing promising candidate genes will to allow us to discover additional polymorphisms perhaps revealing functional variants. However, finding genetic variation alone is insufficient;as we capture the genetic heterogeneity associated with selected sub-phenotypes of this disease, we will develop predictive network models that will be prognostically useful. Public Health Relevance Statement: In sickle cell anemia, patients have very different clinical manifestations and lengths of survival. It is likely that this is influenced by many other genes that affect vascular function and sickle red cell lifespan. We will discover genetic variants that influence these processes and use novel methods to model interactions among genetic variants that can be used to predict the development of complications like pulmonary hypertension, red cell lifespan and mortality.